There have been no established method for treating the commonest viral disease, influenza. Human influenza viruses are classified into types A, B and C, depending on their internal antigens, among which types A and B are known to cause intensive symptoms. Amantadine has been known for more than 20 years as a chemotherapeutic agent, though efficacy thereof has not been evaluated yet. Accordingly, there has been a strong demand for the development of novel and effective anti-influenza agents.
It has been known that microorganisms can produce various useful compounds. For example, Stachybotrys, a fungus is known to produce compounds having pyran fused ring [(1) Japanese Patent Publication (KOKAI) 176782/1993; (2) Japanese Patent Publication (KOKAI) 128266/1994; (3) Japanese Patent Publication (KOKAI) 239869/1994; (4) Japanese Patent Publication (KOKAI) 256350 1994; (5) J. Org. Chem. 57 6700-03 (1992)]. These references, however, merely describe that such compounds have nerve growth factor (NGF) activating effects and are useful for the treatment of Alzheimer's diesease (References 1-4) or that such compounds have antibacterial and antifungal effects (Reference 5). Thus, it has not been known that Stachybotrys produces compounds having antiviral activities.
Further, the following references describe compounds having spiro-type fused ring of tetrahydrofuran ring [(6) Japanese Patent Publication (KOKOKU) 11634/1982 (U.S. Pat. No. 4,229,466); (7) Japanese Patent Publication (KOKOKU) 32170/1987 (U.S. Pat. No. 4,831,053); (8) Japanese Patent Publication (KOKAI) 145161/1995; (9) WO 95/26344]. Among these references, References (6), (7) and (9) merely show that their compounds are useful for the treatment of nephritis, hepatitis, and depression/mania, and the like, and Reference (8) merely shows that the compounds have retrovirus protease inhibitory effects.
Further, it is described that terpenehydroquinone derivatives isolated from poriferan have antiviral effects (WO 91/12250), but which does not disclose the compounds of the present invention.
In addition, natural-type sesquiterpene derivatives producible from strains belonging to the Stachybotrys genus and the synthetic derivatives are described in the PCT application (PCT/JP96/02749, filing date: Sep. 25, 1996, applicant: Shionogi), but which does not describe the compounds of the present invention.
Therefore, the development of novel and effective antiviral agents, in particular, those effective against influenza virus has long been demanded.